ClinVar Miner

Submissions for variant NM_000258.3(MYL3):c.466G>C (p.Val156Leu)

dbSNP: rs199474707
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001052257 SCV001216459 uncertain significance Hypertrophic cardiomyopathy 2019-01-26 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 156 of the MYL3 protein (p.Val156Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV005054321 SCV001245113 uncertain significance Restrictive cardiomyopathy 2018-12-05 criteria provided, single submitter research MYL3 Val156Leu has been previously reported in several HCM cases (Walsh R, et al., 2017; Wang J, et al., 2014; Sao Paulo, Pers. Comm., LMM, Pers. Comm.). We have also identified this variant in a HCM proband and their affected first degree relative, however both individuals also harbour a pathogenic TNNI3 variant. MYL3 Val156Leu is present once in the Genome Aggregation Database (AF= 0.000004, http://gnomad.broadinstitute.org/). Interestingly, different rare variants at this position (c.466G>T Val156Leu & c.466G>A Val156Met) have also been reported in HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. In silico tools SIFT, PolyPhen2 and MutationTaster all predict this variant to be deleterious. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is rare in the general population (PM2), has been identified in more than 2 HCM probands (PS4_Supporting) and in silico tools predict this variant to be deleterious (PP3), therefore we classify MYL3 Val156Leu as a variant of 'uncertain significance'.

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